BIOSIMILARS: What Every Pharmacist Needs to Know

BIOSIMILARS: What Every Pharmacist Needs to Know Edward C. Li, Pharm.D., M.P.H., BCOP University of New England College of Pharmacy Portland, Maine James G. Stevenson, Pharm.D., FASHP University of Michigan College of Pharmacy Visante, Inc. Ann Arbor, Michigan 2 Disclosure Edward C. Li, Pharm.D., M.P.H., BCOP, declares that he has served on an advisory board and speakers bureau for Hospira and an advisory board for Pfizer Inc. He has also served on advisory boards for Merck and Sandoz and has divested himself of these relationships. James G. Stevenson, Pharm.D., FASHP, declares that he has served as a consultant for Amgen Inc. and is an employee of Visante, Inc. Target Audience: Pharmacists and Pharmacy Technicians ACPE#: 0202-0000-16-014-L04-P 0202-0000-16-014-L04-T Activity Type: Knowledge-based The American Pharmacists Association is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. 3 4 Learning Objectives At the completion of knowledge-based activity, participants will be able to: 1. Discuss the current status of biosimilars in the United States, including recent FDA activities. 2. Identify potential implications of biosimilars for pharmacists working in various practice settings, including issues of product substitution and interchangeability. 3. Identify and discuss issues related to both product efficacy and patient safety for biosimilar agents. 4. Discuss strategies for determine appropriate formulary placement for biosimilars. At least one biosimilar application has been submitted to the FDA for: A. Adalimumab B. Trastuzumab C. Cetuximab D. Golimumab 5 6

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Which FDA Guidance Document is forthcoming and has yet to be released in draft form? A. Naming B. Scientific standards C. Interchangeability D. Quality considerations For a biosimilar to be approved, clinical trials should demonstrate: A. Comparability in efficacy between the biosimilar and reference using a clinically sensitive endpoint B. That the biosimilar is safe and effective in all of the reference product s indications C. That the biosimilar is safer than the reference product D. Equivalence in clinical outcomes related to immunogenicity (e.g., rare but serious adverse effects, loss of efficacy) between the biosimilar and reference product 7 8 How does the FDA s interchangeable biosimilar designation impact pharmacist substitution? A. These products require more pharmacovigilance than for standard biosimilars B. Current state pharmacy practice substitution laws allow substitution for interchangeable biosimilars only C. For a reference product where there is more than one interchangeable biosimilar, pharmacists can substitute one interchangeable biosimilar for another D. The interchangeable designation means the pharmacist does not need to notify the prescriber of the substitution Which of the following about the formulary review for biosimilars is true? A. The P&T committee should review the biosimilar data package exactly the same way it reviews other novel agents that are recently FDA-approved B. The P&T committee should utilize the generic policy to add the biosimilar to formulary C. The range of indications for use should be considered when reviewing a biosimilar for formulary consideration D. Product formulation, device/container, packaging/labeling are non-factors to review because the biosimilar will be the same as the reference product in these domains 9 10 The Patent Cliff and Growth Potential for the Biosimilars Market Global Sales 2013, US$ Billion Adalimumab (Humira) 10.7 Infliximab (Remicade) 8.9 Rituximab (Rituxan, Mabthera) 8.6 Etanercept (Enbrel) 8.3 Bevacizumab (Avastin) 7 Trastuzumab (Herceptin) 6.8 Pegfilgrastim (Neulasta) 4.4 0 1 2 3 4 5 6 7 8 9 101112 www.gabionline.net/biosimilars/general/top 8 blockbuster biologicals 2013. www.gabionline.net/biosimilars/general/us 67 billion worth of biosimilarpatents expiring before 2020 (both accessed 2015 Dec 3). EU Expiry Date U.S. Expiry Date 2018 2016 Expired 2018 Expired 2016 Expired 2013/2028* 2022 2019 Expired 2019 2017 Expired *Expiry date uncertain. 11 Background on Drugs & Biologics Drugs are approved under Section 505 of the FDCA NDA: Section 505(b)(2); ANDA: Section 505(j) Biologics are approved under the PHSA Originator/reference/follow on: 351(a); Biosimilar: 351(k) The Biologics Price Competition and Innovation Act was enacted to increase competition with biological medications Decreased prices (or overall expenditures) Increased innovation Several older biologics (e.g., insulins) were approved under Section 505 BPCI allows a transition period to allow approval under Section 505 before 2020 Li EC, et al. J Manag Care Spec Pharm. 2015;21(7):532 39 Blackstone EA et al. Am Health Drug Benefits. 2013; 6:469 78. Heinemann L, et al. Diabetes Technol Ther. 2015;17(7):510 26. 12

Current Status of Biosimilar Activities Biologics: More Complex than Traditional Small Molecule Drugs 2/2012 Three FDA draft guidance documents on biosimilars (Scientific, Quality, Q&A) 5/2014 FDA draft guidance: clinical pharmacology 3/2015 First biosimilar approved 5/2015 FDA draft guidance: Additional Q&A Human EPO 165 amino acids MW ~ 34,000 Da Cisplatin (NH 3 ) 2 PtCl 2 MW ~ 300 Da 2010 2011 2012 2013 2014 2015 3/2010 BPCI Act passed as part of the PPACA 3/2013 Draft guidance on formal meetings with FDA and sponsors 9/2014 Purple book announced 4/2015 Finalized guidance documents from 2/2012 8/2015 FDA draft guidance: naming Biologics Produced by living systems High molecular weight Complex & heterogeneous structure Impossible to fully characterize Sensitive to external conditions & manufacturing changes Relatively high immunogenicity Small-molecule drugs Produced by chemical reactions Relatively low molecular weight Final structure independent of process Able to be characterized fully Stable Mostly non-immunogenic 13 Declerck PJ. GaBI J. 2012; 1:13 6. Illustration courtesy of Olgun Guvench, M.D., Ph.D., University of New England College of Pharmacy. 14 Manufacturing Biosimilars: Sources of Variation Regulatory Definitions of a Biosimilar Food and Drug Administration (U.S.) A biological product that is highly similar to a U.S. licensed reference biological product notwithstanding minor differences in inactive components and for which there are no clinically meaningful differences in safety, purity, or potency of the product European Medicines Agency Europe structurally highly similar versions of an already authorized biological medicinal product (the reference product) with demonstrated similarity in physicochemical characteristics, efficacy, and safety based on a comprehensive comparability exercise Adapted from Mellstedt H et al. Ann Oncol. 2008; 19:411-9. 15 http://www.fda.gov/downloads/drugsguidancecomplianceregulatoryinformati on/guidances/ucm291128.pdf. April 2015 (accessed 2015 Oct 30). Weise M et al. Nat Biotechnol. 2011; 29:690 3. 16 General Principles for Demonstrating Biosimilarity Biosimilars approved via an abbreviated pathway Demonstration of biosimilarity is a comparability exercise and not a therapeutic equivalence study Goal of the biosimilarity exercise is to establish that the candidate biosimilar is not significantly different from the reference product and is unlikely to have any clinically significant differences Smaller scale direct comparisons and extrapolation are used FDA Specifications for Biosimilars Biosimilar Product Specification Formulation Delivery device/container Routes of administration Indications for use Strength Comparison with Reference May be different May be different May obtain licensure for fewer than all routes of administration for which reference product is licensed May obtain licensure for fewer than all conditions of use for which reference product is licensed Must be the same http://www.fda.gov/downloads/drugsguidancecomplianceregulatoryi nformation/guidances/ucm291128.pdf. April 2015 (accessed 2015 Oct 30). 17 http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/ Guidances/UCM444661.pdf. April 2015 (accessed 2015 Oct 30). 18

Biosimilar Development Approach Develop highly similar biologic Analytical methods for structure/function Cell lines In vitro/vivo models Substance pilot and final scale Formulation and final drug product FDA Approval Test and confirm biosimilarity Human clinical trials Consideration of clinically sensitive endpoints Clinically sensitive patient population Immunogenicity Efficacy and safety Postmarketing Monitoring EU Guidance and risk management plans FDA consultation of proposed approach May be mandatory Test and confirm Interchangeability No explicit FDA guidance Will be difficult to do in the initial 351(k) application Demonstrating Biosimilarity: A Stepwise Approach Compare proposed biosimilar to reference in terms of 1. Structure 2. Function 3. Animal Toxicity Studies 4. Human Pharmacokinetics (PK) and Pharmacodynamics (PD) 5. Clinical Immunogenicity 6. Clinical Safety and Effectiveness FDA intends to use a totality of the evidence approach Adapted from McCamish M et al. Clin Pharmacol Ther. 2012; 91:405 17. 19 http://www.fda.gov/downloads/drugsguidancecomplianceregulatoryinformation /Guidances/UCM291128.pdf. April 2015 (accessed 2015 Oct 30). 20 Biosimilar and Biologic Development Structure and Function 351(a) 351(k) Serve as the foundation of biosimilar development Useful in determining what future studies are necessary Structure Amino acid sequence, higher-order structures, glycosylation, pegylation, etc. Analyze lot-to-lot variability Function Evaluate pharmacologic activity via in vitro or in vivo experiments Functional evaluation that compares candidate to reference http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugs aredevelopedandapproved/approvalapplications/therapeuticbiologicapplicati ons/biosimilars/ucm292463.pdf. Feb 15, 2012 (accessed 2015 Oct 30). 21 http://www.fda.gov/downloads/drugsguidancecomplianceregulatoryinform ation/guidances/ucm291128.pdf. April 2015 (accessed 2015 Oct 30). 22 Analytical Characterization: Fingerprinting Four Assessments of Analytical Characterization Studies of Structure and Function: Residual Uncertainty High Not similar No further development through 351(k) Similar Additional information needed: analytical, comparative PK/PD, etc. Highly similar High confidence; appropriate for targeted clinical studies Low Highly similar with fingerprint like similarity Very high confidence; appropriate for more targeted clinical studies http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/dru http://www.fda.gov/downloads/drugsguidancecomplianceregulatoryi gs/advisorycommitteeforpharmaceuticalscienceandclinicalpharmacology/ucm315764.p nformation/guidances/ucm291128.pdf. April 2015 (accessed 2015 Oct df. Aug 8, 2012 (accessed 2015 Oct 30). 23 30). 24

Human Pharmacokinetics and Pharmacodynamics Fundamental for demonstrating biosimilarity Both PK and PD will be necessary PK: patient population considerations PD should study measures that Are relevant to clinical outcomes Can be quickly assessed with precision Have the sensitivity to detect clinically meaningful difference Ideally correlate exposure to clinical outcomes Use crossover and parallel designs Comparative Clinical Studies Efficacy and safety: specific clinical trial design will depend on what residual questions remain Clinical studies should be designed to demonstrate neither decreased nor increased activity Use clinically relevant and sensitive endpoints in the right population Biosimilar sponsor to justify comparability delta http://www.fda.gov/downloads/drugsguidancecomplianceregulatoryinformation /Guidances/UCM291128.pdf. April 2015 (accessed 2015 Oct 30). 25 Schellekens H. NDT Plus. 2009; 2(suppl 1):i27 i36. 26 Clinical Trial Design: Equivalence Indication Extrapolation Framework Establish the equivalence margin (δ) via the 95 95 method 95% CI should fall between δ and +δ for equivalence Patient Factors Similarity of biologic disposition: PK/PD Organ function Age, ethnicity, etc. Disease Factors Clear MOA? Similarity of disease (e.g., histology, stage, pathophysiology, etc.) Single vs. combo therapy Clinical manifestation Endpoint Factors Efficacy and toxicity Short term vs. longterm Sensitivity of surrogate outcomes However, non inferiority studies may be appropriate if it is wellestablished that the biologic saturates the receptors at the clinical dose Quantitative Evidence of Biosimilarity In vitro, preclinical, epidemiological studies, diagnostic studies, clinical trials, and observational studies Indication Extrapolation Determination No extrapolation; extrapolation to some indications; extrapolation to all indications Adapted from Dranitsaris G et al. Invest New Drugs. 2013; 31:479 87 and Greene CJ et al. J Trauma Stress. 2008; 21:433 9. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformatio n/guidances/ucm291128.pdf. April 2015 (accessed 2015 Oct 30). 27 http://www.ema.europa.eu/docs/en_gb/document_library/scientific_guidelin e/2013/04/wc500142358.pdf (accessed 2015 Nov 4). Weise M et al. Blood. 2014; 124:3191 6. 28 Immunogenicity Concerns All biologics confer a risk of immunogenicity Related to patient, disease, and product factors Consequences include neutralizing antibodies or cytokine release Scientific tools for detecting immunogenicity exist, but they do not always translate to clinical outcomes Immunogenicity concerns Clinical consequences: Loss or diminished efficacy or safety Case reports of rare but serious adverse reactions have been reported Changes to the structure of the protein increase variation in immunogenicity Lot-to-lot and between manufacturers Variations in manufacturing must be minimized U.S. FDA. Immunogenicity Assessment for Therapeutic Protein Products. August 2014. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformatio n/guidances/ucm338856.pdf 29 29 Clinical immunogenicity assessment for biosimilars Goal is to evaluate potential differences in incidence and severity of immune responses using endpoints such as antibody formation (binding, neutralizing), cytokine levels, etc. FDA recommends a comparative parallel study U.S. FDA. Immunogenicity Assessment for Therapeutic Protein Products. August 2014. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidanc es/ucm338856.pdf Schellekens H. NDT Plus. 2009; 2(suppl 1):i27-i36. 30

Biosimilar Pharmacovigilance FDA Approval Pharmacovigilance Practical to encourage healthcare provider reporting Real-time data Ensure traceability Healthcare Provider Responsibility for Reporting Correct attribution of safety event Maintenance of electronic medical record Bar code administration Medication reconciliation Consideration of transitions of care Risk Identification and Characterization Risk minimization Healthcare provider communication Recalls and alerts FDA REMS? Interchangeability Appropriate to be substituted for the reference product without the intervention of the healthcare provider who prescribed the reference product Standards for determining interchangeability Must be a biosimilar Produces same clinical result as the reference in any given patient Risk of harm or diminished efficacy due to alternating or switching between biosimilar and reference is no more than using the reference product with no switching Will be difficult in the initial 351(k) application due to the sequential nature of the assessment FDA is in process of developing guidance Zuñiga L et al. Pharmacoepidemiol Drug Saf. 2010; 19:661-9. Felix T et al. Nat Biotechnol. 2014; 32:128-30. Casadevall N et al. Expert Opin Biol Ther. 2013; 13:1039-47. 31 http://www.fda.gov/downloads/drugsguidancecomplianceregulatoryinformati on/guidances/ucm291128.pdf. http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformatio n/ucm216146.pdf 32 There Will Be Many Types of Biologic Products Description Data package Practice Implications 351(a) Originator First-to market biologic molecule; will likely be the reference product Demonstrate safety & efficacy 351(k) Biosimilar Highly similar to reference product; approved via biosimilars pathway Abbreviated data package Biosimilar reimbursement per CMS (same margin as reference) 351(k) Interchangeable Biosimilar A biosimilar that can be switched to and from the reference with no clinical consequences Abbreviated data package, more information on switching Biosimilar reimbursement per CMS; possible automatic substitution without contacting prescriber 351(a) Nonoriginator biologic It is another brand name of an already approved biologic Demonstrate safety & efficacy Lower margin if lower cost; automatic substitution issues 351(a) Nextgeneration Bio-better Biologic that has been altered to achieve improved clinical outcomes Demonstrate safety & efficacy New entity 33 Biosimilar User Fee Act (BsUFA) Reauthorization BsUFA allows the FDA to collect user fees in return for a timely review of the application Performance goals: Review and act on 85% (FY2016) and 90% (FY 2017) of original biosimilar applications within 10 months of receipt and Review and act on 85% (FY2016) and 90% (FY 2017) of resubmitted biosimilar applications within 6 months of receipt 90% in 10 months for original supplements and in 6 months for resubmitted supplements with clinical data http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdru gsaredevelopedandapproved/approvalapplications/therapeuticbiologicappl ications/biosimilars/ucm281991.pdf 34 Biosimilar Applications to the FDA FDA has been busy BsUFA Workload and Volume: Interim Report. http://www.fda.gov/downloads/forindustry/userfees/biosimilaruser FeeActBsUFA/UCM459686.pdf 35 BsUFA Workload and Volume: Interim Report. http://www.fda.gov/downloads/forindustry/userfees/biosimilaruser FeeActBsUFA/UCM459686.pdf 36

Biosimilar Applications and FDA Staff Involved Additional 351(k) BLA Applications Pegfilgrastim (Sandoz) 11/18/2015 http://www.gabionline.net/biosimilars/news/fda-acceptsapplication-for-pegfilgrastim-biosimilar Adalimumab (Amgen) 11/27/2015 http://www.gabionline.net/biosimilars/news/amgensubmits-biosimilar-adalimumab-application-to-fda BsUFA Workload and Volume: Interim Report. http://www.fda.gov/downloads/forindustry/userfees/biosimilaruser FeeActBsUFA/UCM459686.pdf 37 38 Insulin: Biosimilar or Follow-on? Labor Estimates Basaglar is the first insulin product approved through an abbreviated approval pathway under the Federal Food, Drug, and Cosmetic Act. A 505(b)(2) application was submitted for Basaglar that relied, in part, on the FDA s finding of safety and effectiveness for Lantus (insulin glargine injection) to support approval. The applicant demonstrated that Basaglar was sufficiently similar to Lantus to scientifically justify reliance, and also provided Basaglar-specific data to establish the drug s safety and efficacy for its approved uses. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm477734.htm 39 BsUFA Workload and Volume: Interim Report. http://www.fda.gov/downloads/forindustry/userfees/biosimilaruser FeeActBsUFA/UCM459686.pdf 40 BsUFA Reauthorization: Public Meeting on 12/18/2015 Practice Implications: Mabs Not a biosimilar policy negotiation Theme: how can the FDA ensure timely review? Eight 351(k) BLA applications Action date passed for 5; 1 approval; 1 complete response letter Lots of time spent on developing biosimilar policy Cancer Bevacizumab Trastuzumab Inflammation Adalimumab Etanercept Infliximab High Impact on: Physician clinics Hospital outpatient infusion centers Specialty pharmacy FDA needs to hire and retain scientists that can work on biosimilars, particularly as they are highly sought-after by industry, which offers more competitive salaries. Rituximab Clinics Hospitals Specialty Rx Etanercept (Sandoz) 9/10/2015 http://www.gabionline.net/biosimilars/news/fda-acceptsapplication-for-etanercept-biosimilar http://www.raps.org/regulatory- Focus/News/2015/12/18/23792/Biosimilar-User-Fees-Public- Meeting-Kicks-Off-Negotiations-for-BsUFA-II/ 41 42

Practice Implications: non-mabs Filgrastim, Pegfilgrastim, Epoetin What Is the Desired Use of the Biosimilar? Reference biologic labeled indications Appropriate indications Biosimilar labeled indications Desired use within institution Clinics Hospitals Specialty Rx Pharmacies Insulins 43 P&T determination Must incorporate patient, disease, and endpoint factors with biosimilarity data 44 Key Takeaways There is a robust pathway for the approval of biosimilars in the US There is currently one FDA approved biosimilar and another product approved under Section 505 allowed via the BPCI Act during the transition period before 2020 The FDA has been busy writing policy and is overworked with sponsor meetings and reviewing applications Useful Resources NCCN biosimilars white paper Zelenetz AD, Ahmed I, Braud EL et al. J Natl Compr Canc Netw. 2011; 9(suppl 4):S1 22. Biosimilars: the science of extrapolation Weise M, Kurki P, Wolff Holz E et al. Blood. 2014; 124:3191 6. Pharmacist substitution of biological products Li E, Ramanan S, Green L et al. J Manag Care Spec Pharm. 2015; 21:532 9. 45 46 % of Drugs in U.S. Market Growing Role of Biologics in Pipeline 100% 11% 11% 80% 60% 89% 89% 40% 20% 0% in Market Small Molecules 38% 38% 62% in Phase III Biologicals Biological Prescription Cost Implications in U.S. Biologicals and specialty pharmaceuticals are the fastest growing pharmaceutical expense in the U.S. The Economist estimates that biologics could make up 32% of total big pharma sales by 2023 7 of top 10 drugs by sales in 2014 were biologics Significant interest on the part of payers/employer groups in managing the specialty cost trend Estimate savings of approximately 20% 30% Source: IMS Data, December 2010. 47 http://www.imshealth.com/deployedfiles/imshealth/global/content/ Healthcare/Life%20Sciences%20Solutions/Generics/IMSH_Biosimilars_WP.pdf (accessed 2015 Dec 26). http://www.economist.com/news/business/21637387 wave new medicines known biologicswill be good drugmakers may not be so good (accessed 2015 Dec 26). 48

Why are Biologics Important? Significant Impact of Biosimilars on Pharmaceutical Expense Trend Estimate of $250 billion savings in U.S. over next 10 years from just 11 biosimilar products (Express Scripts) 2008 Congressional Budget Office (CBO) estimated a $25 billion reduction in U.S. expenditures on biologics by 2018 Rand Corporation (2014) predicts that biosimilars will lead to a $44.2 billion reduction (range $13B $66B) in direct spending on biologic drugs from 2014 to 2024 There will be significant pressure from payers to use biosimilars to control healthcare costs Schumock GT et al. Am J Health Syst Pharm. 2015; 72:717 36. 49 http://lab.express scripts.com/insights/industry updates/the $250 billion potential ofbiosimilars. (accessed 2015 Dec 26). https://www.cbo.gov/publication/24808 (accessed 2015 Dec 26. http://www.rand.org/content/dam/rand/pubs/perspectives/pe100/pe127/rand_pe127.pdf (accessed 2015 Dec 26). 50 Prescription Benefit Implications in U.S. Expect plans to use established formulary review processes to review each drug on its own merit If two drugs are considered therapeutically equivalent, the plan will decide benefit tier, prior authorization requirements, and payment policies For infused therapies, CMS has already normalized the margin between the reference biologic and biosimilars (removed financial disincentive to use of biosimilars) Plans likely to use patient financial incentives to drive the use of biosimilars (tiered copayments/co insurance) https://www.cov.com/~/media/files/corporate/publications/2015/04/c ms_releases_new_reimbursement_guidance_for_biosimilars.pdf (Accessed 2015 Dec 26). 51 The Patent Cliff and Growth Potential for the Biosimilars Market Global Sales 2013, US$ Billion Adalimumab (Humira) 10.7 Infliximab (Remicade) 8.9 Rituximab (Rituxan, Mabthera) 8.6 Etanercept (Enbrel) 8.3 Bevacizumab (Avastin) 7 Trastuzumab (Herceptin) 6.8 Pegfilgrastim (Neulasta) 4.4 EU Expiry Date U.S. Expiry Date 2018 2016 Expired 2018 Expired 2016 Expired 2013/2028* 2022 2019 Expired 2019 2017 Expired 0 1 2 3 4 5 6 7 8 9 101112 *Expiry date uncertain. www.gabionline.net/biosimilars/general/top 8 blockbuster biologicals 2013. www.gabionline.net/biosimilars/general/us 67 billion worth of biosimilarpatents expiring before 2020 (both accessed 2015 Dec 26). 52 Current Biosimilars(?) in the US Product enoxaparin US Approval Pathway 505(b)(2)- abbreviated pathway under FDCA US Biosimilar No EU Biosimilar Yes tbo-filgrastim 531(a) No Yes filgastim-sndz 531(k) Yes Yes Insulin glargine 505(b)(2) No Yes Biosimilar Development in the US Brand Name (US or EU) INN Manufacturer abla submitted FDA approval Zarxio filgrastim-sndz Sandoz 7/2014 3/2015 Remsima infliximab Celltrion 8/2014 pegfilgrastim Apotex Sandoz 12/2014 11/2015 Retacrit epoetin zeta Hospira 1/2015 Grastofil filgrastim Apotex 2/2015 etanercept Sandoz 10/2015 adalimumab Amgen 11/2015 53 http://www.gabionline.net/biosimilars/news/. Accessed 2015 Dec 26. 54

Considerations for Formulary Selection of Biosimilars Efficacy/Safety Clinical data Range of indications Immunogenicity concerns Potential for therapeutic interchange Number of similar agents on formulary Pharmaco vigilance requirements Manufacturer Considerations Supply reliability History of drug shortages Supply chain security Anti counterfeit measures Patient assistance programs Reimbursement support Product Considerations Product packaging and labeling Bar coding Compatibility with CSTDs,* robotics Product preparation and administration Storage requirements Hospital and Patient Factors Economic considerations Hospital Payer Patient Payer policies Transitions of care IT and medication system changes Educational requirements Formulary Selection Considerations: Efficacy and Safety Clinical data and populations studied in FDA approval Range of indications Presence of biomarker to assess efficacy and safety Experienced vs. de novo patients Immunogenicity concerns due to switching *CSTDs = closed system transfer devices Griffith N et al. Hosp Pharm. 2014; 49:813 25. 55 Griffith N et al. Hosp Pharm. 2014; 49:813 25. 56 Extrapolation of Indications Extrapolation of data from a clinical trial in one disease to support approval for additional indications Factors to be considered Clinical experience with the reference product Mechanism(s) of action in each indication Target receptors Product structure and target/receptor interactions Pharmacokinetics in different patient populations Differences in the safety/immunogenicity profile between indications Available G-CSFs in the US and Approved Indications Filgrastim (Neupogen ) Tbo-filgrastim (Granix ) Filgrastim-sndz (Zarxio ) Peg-filgrastim (Neulasta ) Approval Pathway BLA BLA Biosimilar 351(k) BLA Reference Product None None Filgrastim none Cancer patients receiving myelosuppressive chemotherapy Patients with acute myeloid leukemia receiving induction or consolidation chemotherapy --- --- Cancer patients receiving bone marrow transplant Patients undergoing peripheral blood progenitor cell collection and therapy Patients with severe chronic neutropenia --- --- --- --- --- --- Weise M et al. Blood. 2014; 124:3191 6. http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsare developedandapproved/approvalapplications/therapeuticbiologicapplications/biosi milars/ucm428732.pdf(accessed 2015 Dec 26). 57 58 Formulary Selection Considerations: Manufacturer Considerations Expertise manufacturing biologics Supply reliability Supply security and anti counterfeit measures Patient assistance programs Reimbursement support programs Formulary Selection Considerations: Product Considerations Product packaging and labeling from safety perspective Bar coding Compatibility with closed system transfer devices (if NIOSH hazardous drug) Preparation and administration considerations Storage requirements Dosage forms meet needs of patient populations Griffith N et al. Hosp Pharm. 2014; 49:813 25. 59 Griffith N et al. Hosp Pharm. 2014; 49:813 25. 60

Formulary Selection Considerations: Payer, Provider, and Patient Factors Economic considerations Payer Provider Patient out of pocket cost impact on adherence Management of transitions of care How many products in preferred status Consistency of product provided Will P&T Committees review a biosimilar through the routine P&T process or handle like a generic? a. Full P&T review b. Abbreviated review c. Manage like a generic 61 62 Operational Challenges: Financial Analysis Pricing information comparison (provider, payer) Portfolio pricing Reimbursement implications for healthcare provider Patient assistance and out of pocket expenses Determine financial impact from various perspectives Do you think that formularies will only have one biologic in a therapeutic category, or will there be both the reference product and biosimilar(s)? a. Only the reference product b. Only a biosimilar c. Both Lucio SD et al. Am J Health Syst Pharm. 2013; 70:2004 17. 63 64 Do you think that formularies will only have one biologic in a therapeutic category, or will there be both the reference product and biosimilar(s)? a. Only the reference product b. Only a biosimilar c. Both If more than one, under what circumstances will each be used? How do you think formulary systems will manage biosimilars and reference products? a. Biosimilar preferred for all patients through copay tiers or co insurance b. Biosimilar preferred for new starts only, with reference product available at preferred tier for existing patients c. Reference product on par with biosimilar choice up to prescriber with no patient incentives d. Unsure 65 66

If a biosimilar is added to an inpatient formulary, will a therapeutic interchange be used for patients who are admitted on the reference product? a. Yes b. No c. Unsure If an interchange is done, how will patients be informed/educated? Operational Challenges: Information Systems Differentiate between similar biologics in electronic systems Pharmacy information systems CPOE and eprescribing systems Dispensing systems and automation emar Order sets, protocols Medication reconciliation Patient s own home medicine 67 Lucio SD et al. Am J Health Syst Pharm. 2013; 70:2004 17. 68 Operational Challenges: Inventory Management Purchaser needs adequate information (NDC, etc.) Will multiple products be stocked? Reference and biosimilar Multiple biosimilars Product storage, placement on shelf, etc. Inventory costs Wrong product dispensing errors Interchangeability The biological is biosimilar to the reference product and can be expected to produce the same clinical result as the reference product in any given patient, and the risk in terms of safety or diminished efficacy of alternating or switching between use of the product and its reference product is not greater than the risk of using the reference product without such alteration or switch State substitution laws will impact practice Lucio SD et al. Am J Health Syst Pharm. 2013; 70:2004 17. 69 http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ ucm290967.htm. http://www.ncsl.org/research/health/state laws and legislation related to biologicmedications and substitution of biosimilars.aspx (both accessed 2015 Dec 26). 70 Operational Challenges: Product Substitution State legislation to clarify pharmacist authority to substitute FDA Purple Book Challenges Care transitions Medication reconciliation Differences between federal and state regulations Purple Book: Lists of Licensed Biological Products with Reference Product Exclusivity and Biosimilarity or Interchangeability Evaluations Designed to enable a user to determine if a biological product is biosimilar or interchangeable with a reference biologic per FDA evaluation Cross references biological products licensed under 351(a) with biosimilar or interchangeable products licensed under 351(k) http://www.ncsl.org/research/health/state laws and legislation related to biologic medicationsand substitution of biosimilars.aspx. (Accessed 2015 Dec 26). http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/a pprovalapplications/therapeuticbiologicapplications/biosimilars/ucm411424.htm. (Accessed 2015 Dec 26). 71 http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredev elopedandapproved/approvalapplications/therapeuticbiologicapplications/ Biosimilars/ucm411418.htm (accessed 2015 Dec 26). 72

Typical Features of State Legislation Prescriber can prevent substitution with DAW Prescriber must be notified of substitution Patient must be notified and consent Records of substitution must be retained State should keep a list of interchangeable products http://www.ncsl.org/research/health/state laws and legislation related tobiologic medications and substitution of biosimilars.aspx (accessed 2015 Dec 26). 73 http://www.ncsl.org/research/health/state laws and legislationrelated to biologic edications and substitution of biosimilars.aspx (accessed 2015 Dec 26). 74 Pharmacovigilance Important to assure safety Consider risks seen in reference product Are there any new safety concerns? Population based assessments gives larger n to identify rare safety concerns Might be mandatory for some products How will products be differentiated for pharmacovigilance purposes? The Conundrum of Biosimilar Naming Biosimilars should have the exact same INN as the reference product Pros Communicate that these products are highly similar Facilitate adoption and substitution of interchangeable biologics Cons Hard to trace for pharmacovigilance Biosimilars should have a distinct INN to differentiate from reference and other biosimilars Pros Improved pharmacovigilance Recognize as distinct products Cons Confusion about whether they are interchangeable May impede adoption Issues with substitution http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation Traynor K. Am J Health-Syst Pharm. 2014; 71:446-7. /Guidances/ucm290967.htm (accessed 2015 Dec 26). 75 Carroll J. Manag Care. 2013; 22:6-7. 76 Biosimilar Naming Precedent WHO proposed guidance Biological qualifier: INN + 4 letter, randomly assigned suffix EMA approved with identical INN; differentiated with brand names Filgrastim in the U.S. (approved indications vary) Filgrastim (reference biologic, Neupogen) tbo filgrastim (not biosimilar [351(a)], Granix) Filgrastim sndz (biosimilar [351(k), Zarxio) http://www.who.int/medicines/services/inn/bq_innproposal201407.pdf. Revised July 2014. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseact ion=search.search_drug_name (both accessed 2015 Dec 26). 77 FDA Proposed Guidance on Naming INN with an added random four letter suffix for all biologics (including reference products) replicamab cznm replicamab hixf Benefits Ability to differentiate products for pharmacovigilance purposes Common INN will group similar biologics in electronic systems Having suffix for all products reduces perception that biosimilar is inferior to reference product http://www.fda.gov/downloads/drugs/guidancecomplianceregulator yinformation/guidances/ucm459987.pdf. August 2015 (accessed 2015 Dec 26). 78

FDA Proposed Guidance on Naming Concerns Unless interchangeable biosimilar has the same suffix, it will inhibit interchange Potential for errors when using four letter suffix devoid of meaning (alternative to represent manufacturer) More complex naming system increases likelihood that errors could occur, actually harming pharmacovigilance Need to change name of current biologics on market creates confusion http://www.healio.com/rheumatology/psoriatic arthritis/news/online/%7bfd74beb9 177e 4618 8a94 aab7cd3f77b7%7d/physician groups support proposed fda biosimilar naming conventionbut also call for maker id http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm 459987.pdf. August 2015 (Both accessed 2015 Dec 26). 79 What strategies will you use to track the appropriate product the patient is taking in your electronic systems and during medication reconciliation? a. Order & document with full product name (INN plus suffix) b. Order & document with full product name PLUS brand name c. Order and document with INN (minus suffix) PLUS brand name d. Other 80 Operational Challenges: Education Education of all providers to avoid confusion (clinical information, policies, appropriate use, etc.) Patient education Managing transitions of care. Recommendations for Biosimilars for Pharmacists Use existing formulary system and processes to evaluate for formulary inclusion Carefully consider scope of indications for use Conduct sophisticated economic analysis, considering costs, reimbursement, and patient impact Prepare IT systems to facilitate effective pharmacovigilance programs Consider processes for transitions of care Meet educational needs of patients and providers Lucio SD et al. Am J Health Syst Pharm. 2013; 70: 2004 17. 81 82 Resources for Pharmacists and Technicians ASHP Resource Center on Biosimilars http://www.ashp.org/menu/practicepolicy/resourcecenters /Emerging Sciences/Biosimilars.aspx (accessed 2015 Oct 30). American Journal of Managed Care Resource Center http://www.ajmc.com/resource center/biosimilars (accessed 2015 Oct 30). Lucio SD, Stevenson JG, Hoffman JM. Biosimilars: implications for health system pharmacists. Am J Health Syst Pharm. 2013; 70:2004 17. Key Points Biologics are complex drugs that are not considered generic ; still waiting for guidance on interchangeable biosimilars The FDA approval process to demonstrate that a biosimilar is highly similar to a reference biologic is scientific, robust, and regulated No specific safety issues have been identified for approved and marketed biosimilars in Europe Incorporation of biosimilars into clinical practice offers cost savings and increased patient access 83 84

Key Points Integration of biosimilar agents into clinical practice presents many operational and clinical challenges European biosimilar experience has been good Federal and state regulatory actions, pricing, and reimbursement policies will play key roles in determining future use of biosimilars and product selection in the U.S. Key Points Transitions of care and medication reconciliation will be ongoing practice management issues Key issues yet to be resolved include naming, interchangeability criteria and requirements, and pharmacovigilance requirements Pharmacists should assume leadership in planning a strategy for successful operational and clinical use of these agents 85 86 At least one biosimilar application has been submitted to the FDA for: A. Adalimumab B. Trastuzumab C. Cetuximab D. All of the above Which FDA Guidance Document is forthcoming and has yet to be released in draft form? A. Naming B. Scientific standards C. Interchangeability D. All of the above 87 88 For a biosimilar to be approved, clinical trials should demonstrate: A. Comparability in efficacy between the biosimilar and reference using a clinically sensitive endpoint B. That the biosimilar is safe and effective in all of the reference product s indications C. That the biosimilar is safer than the reference product D. Equivalence in clinical outcomes related to immunogenicity (e.g., rare but serious adverse effects, loss of efficacy) between the biosimilar and reference product At least one biosimilar application has been submitted to the FDA for: A. Adalimumab B. Trastuzumab C. Cetuximab D. Golimumab 89 90